TY - JOUR
T1 - Complex phenotype of dyskeratosis congenita and mood dysregulation with novel homozygous RTEL1 and TPH1 variants
AU - Ungar, Rachel A.
AU - Giri, Neelam
AU - Pao, Maryland
AU - Khincha, Payal P.
AU - Zhou, Weiyin
AU - Alter, Blanche P.
AU - Savage, Sharon A.
N1 - Funding Information:
and Ann Carr, MS, CGC provided study support through contract HHSN261201100018C with Westat, Inc. (Rockville, MD). The NCI’s Division of Cancer Epidemiology and Genetics Exome Sequencing Working Group is acknowledged for providing in house control samples for variant comparisons. We also thank Dr. Francis McMahan, National Institute of Mental Health, for reviewing genomic regions of interest. This work was supported by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute National Institutes of Health, and by the intramural research program of the National Institute of Mental Health, National Institutes of Health.
Funding Information:
We thank the patient and his family for their valuable participation?in our study. Lisa Leathwood, RN, Maureen Risch, RN, and Ann Carr, MS, CGC provided study support through contract HHSN261201100018C with Westat, Inc. (Rockville, MD). The NCI's Division of Cancer Epidemiology and Genetics Exome Sequencing Working Group is acknowledged for providing in house control samples for variant comparisons. We also thank Dr. Francis McMahan, National Institute of Mental Health, for reviewing genomic regions of interest. This work was supported by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute National Institutes of Health, and by the intramural research program of the National Institute of Mental Health, National Institutes of Health.
Publisher Copyright:
© 2018 Wiley Periodicals, Inc.
PY - 2018/6
Y1 - 2018/6
N2 - Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome caused by germline mutations in telomere biology genes. Patients have extremely short telomeres for their age and a complex phenotype including oral leukoplakia, abnormal skin pigmentation, and dysplastic nails in addition to bone marrow failure, pulmonary fibrosis, stenosis of the esophagus, lacrimal ducts and urethra, developmental anomalies, and high risk of cancer. We evaluated a patient with features of DC, mood dysregulation, diabetes, and lack of pubertal development. Family history was not available but genome-wide genotyping was consistent with consanguinity. Whole exome sequencing identified 82 variants of interest in 80 genes based on the following criteria: homozygous, <0.1% minor allele frequency in public and in-house databases, nonsynonymous, and predicted deleterious by multiple in silico prediction programs. Six genes were identified likely contributory to the clinical presentation. The cause of DC is likely due to homozygous splice site variants in regulator of telomere elongation helicase 1, a known DC and telomere biology gene. A homozygous, missense variant in tryptophan hydroxylase 1 may be clinically important as this gene encodes the rate limiting step in serotonin biosynthesis, a biologic pathway connected with mood disorders. Four additional genes (SCN4A, LRP4, GDAP1L1, and SPTBN5) had rare, missense homozygous variants that we speculate may contribute to portions of the clinical phenotype. This case illustrates the value of conducting detailed clinical and genomic evaluations on rare patients in order to identify new areas of research into the functional consequences of rare variants and their contribution to human disease.
AB - Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome caused by germline mutations in telomere biology genes. Patients have extremely short telomeres for their age and a complex phenotype including oral leukoplakia, abnormal skin pigmentation, and dysplastic nails in addition to bone marrow failure, pulmonary fibrosis, stenosis of the esophagus, lacrimal ducts and urethra, developmental anomalies, and high risk of cancer. We evaluated a patient with features of DC, mood dysregulation, diabetes, and lack of pubertal development. Family history was not available but genome-wide genotyping was consistent with consanguinity. Whole exome sequencing identified 82 variants of interest in 80 genes based on the following criteria: homozygous, <0.1% minor allele frequency in public and in-house databases, nonsynonymous, and predicted deleterious by multiple in silico prediction programs. Six genes were identified likely contributory to the clinical presentation. The cause of DC is likely due to homozygous splice site variants in regulator of telomere elongation helicase 1, a known DC and telomere biology gene. A homozygous, missense variant in tryptophan hydroxylase 1 may be clinically important as this gene encodes the rate limiting step in serotonin biosynthesis, a biologic pathway connected with mood disorders. Four additional genes (SCN4A, LRP4, GDAP1L1, and SPTBN5) had rare, missense homozygous variants that we speculate may contribute to portions of the clinical phenotype. This case illustrates the value of conducting detailed clinical and genomic evaluations on rare patients in order to identify new areas of research into the functional consequences of rare variants and their contribution to human disease.
KW - GDAP1L1
KW - LRP4
KW - RTEL1
KW - SCN4A
KW - STPBN5
KW - TPH1
KW - dyskeratosis congenital
KW - mood dysregulation
UR - http://www.scopus.com/inward/record.url?scp=85046026282&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046026282&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.38706
DO - 10.1002/ajmg.a.38706
M3 - Article
C2 - 29696773
AN - SCOPUS:85046026282
SN - 1552-4825
VL - 176
SP - 1432
EP - 1437
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 6
ER -